Prior to work carried out by the present inventors the structure and characteristics of cell surface receptors for the Fc portion of immunoglobulin (FcR) were not known to any significant degree. The present inventors were the first to clone and characterize a FcR. It is now known that FcR are expressed on most hematopoietic cells, and through the binding of IgG play a key role in homeostasis of the immune system and host protection against infection. By way of example Fc.sub..gamma. RII is a low affinity receptor for IgG that essentially binds only IgG immune complexes and is expressed on a diverse range of cells such as monocytes, macrophages, neutrophils, eosinophils, platelets and B cells (1-3). Fc.sub..gamma. RII is involved in a number of immune related responses including antibody-dependent cell-mediated cytotoxicity, clearance of immune complexes, release of inflammatory mediators and regulation of antibody production (1-6).
Similarly, Fc receptors for other classes of immunoglobulin also occur. For example the Fc receptor for IgE is present on mast cells, basophils and Langerhans cells.
Both the IgG and the IgE Fc receptors contain an extracellular Ig-interactive region which comprises two Ig-like disulfide bonded extracellular domains of the C2 set (7-11). These domains are structurally conserved in all the Ig-superfamily leukocyte FcR (including Fc.sub..gamma. RI, Fc.sub..gamma. RIII, Fc.sub..epsilon.,RI and Fc.alpha.RI) and presumably represents an Ig-interactive motif (12-16). In previous studies the inventors identified the IgG binding region of human Fc.sub..gamma. RII (17, 18). Chimeric Fc.sub..gamma. RII/Fc.sub..epsilon. RI .alpha. chain receptors were used to demonstrate that the second extracellular domain of Fc.sub..gamma. RII was responsible for the binding of IgG, with a direct binding region located between residues Asn.sup.154 to Ser.sup.61. Molecular modelling of Fc.sub..gamma. RII domain 2 predicted a structure comprising 7.beta., strands (A, B, C, C', E, F, G) forming two antiparallel .beta. sheets (containing the ACFG and BC'E strands respectively), stabilized by a disulfide bond between strands B and F and a core of hydrophobic residues (20). The Asn.sub.154 to Ser.sup.161 binding region was shown to encompass an exposed loop region (the F-G loop) at the interface of domains 1 and 2.
In work leading up to the present invention, the inventors cloned and characterized the genes encoding mouse and human Fc receptors. They also surprisingly discovered that alteration of amino acid residues in the Fc receptors lead to altered affinities for immunoglobulin.